Upregulation of pulmonary tissue factor, loss of thrombomodulin and immunothrombosis in SARS-CoV-2 infection
Background: SARS-CoV-2 infection is associated with thrombotic and microvascular complications. The cause of coagulopathy in the disease is incompletely understood. Methods: A single-center cross-sectional study including 66 adult COVID-19 patients (40 moderate, 26 severe disease), and 9 controls, p...
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doaj-b17b1d0611c3414abfb5f9cf23033c622021-09-25T05:10:56ZengElsevierEClinicalMedicine2589-53702021-09-0139101069Upregulation of pulmonary tissue factor, loss of thrombomodulin and immunothrombosis in SARS-CoV-2 infectionIvo M.B. Francischetti0Kevin Toomer1Yifan Zhang2Jayesh Jani3Zishan Siddiqui4Daniel J. Brotman5Jody E. Hooper6Thomas S. Kickler7Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Corresponding author.Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDepartment of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, United StatesDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesBackground: SARS-CoV-2 infection is associated with thrombotic and microvascular complications. The cause of coagulopathy in the disease is incompletely understood. Methods: A single-center cross-sectional study including 66 adult COVID-19 patients (40 moderate, 26 severe disease), and 9 controls, performed between 04/2020 and 10/2020. Markers of coagulation, endothelial cell function [angiopoietin-1,-2, P-selectin, von Willebrand Factor Antigen (WF:Ag), von Willebrand Factor Ristocetin Cofactor, ADAMTS13, thrombomodulin, soluble Endothelial cell Protein C Receptor (sEPCR), Tissue Factor Pathway Inhibitor], neutrophil activation (elastase, citrullinated histones) and fibrinolysis (tissue-type plasminogen activator, plasminogen activator inhibitor-1) were evaluated using ELISA. Tissue Factor (TF) was estimated by antithrombin-FVIIa complex (AT/FVIIa) and microparticles-TF (MP-TF). We correlated each marker and determined its association with severity. Expression of pulmonary TF, thrombomodulin and EPCR was determined by immunohistochemistry in 9 autopsies. Findings: Comorbidities were frequent in both groups, with older age associated with severe disease. All patients were on prophylactic anticoagulants. Three patients (4.5%) developed pulmonary embolism. Mortality was 7.5%. Patients presented with mild alterations in the coagulogram (compensated state). Biomarkers of endothelial cell, neutrophil activation and fibrinolysis were elevated in severe vs moderate disease; AT/FVIIa and MP-TF levels were higher in severe patients. Logistic regression revealed an association of D-dimers, angiopoietin-1, vWF:Ag, thrombomodulin, white blood cells, absolute neutrophil count (ANC) and hemoglobin levels with severity, with ANC and vWF:Ag identified as independent factors. Notably, postmortem specimens demonstrated epithelial expression of TF in the lung of fatal COVID-19 cases with loss of thrombomodulin staining, implying in a shift towards a procoagulant state. Interpretation: Coagulation dysregulation has multifactorial etiology in SARS-Cov-2 infection. Upregulation of pulmonary TF with loss of thrombomodulin emerge as a potential link to immunothrombosis, and therapeutic targets in the disease. Funding: John Hopkins University School of Medicine.http://www.sciencedirect.com/science/article/pii/S2589537021003497ThrombosisHemostasisCoagulationIxolaris |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ivo M.B. Francischetti Kevin Toomer Yifan Zhang Jayesh Jani Zishan Siddiqui Daniel J. Brotman Jody E. Hooper Thomas S. Kickler |
spellingShingle |
Ivo M.B. Francischetti Kevin Toomer Yifan Zhang Jayesh Jani Zishan Siddiqui Daniel J. Brotman Jody E. Hooper Thomas S. Kickler Upregulation of pulmonary tissue factor, loss of thrombomodulin and immunothrombosis in SARS-CoV-2 infection EClinicalMedicine Thrombosis Hemostasis Coagulation Ixolaris |
author_facet |
Ivo M.B. Francischetti Kevin Toomer Yifan Zhang Jayesh Jani Zishan Siddiqui Daniel J. Brotman Jody E. Hooper Thomas S. Kickler |
author_sort |
Ivo M.B. Francischetti |
title |
Upregulation of pulmonary tissue factor, loss of thrombomodulin and immunothrombosis in SARS-CoV-2 infection |
title_short |
Upregulation of pulmonary tissue factor, loss of thrombomodulin and immunothrombosis in SARS-CoV-2 infection |
title_full |
Upregulation of pulmonary tissue factor, loss of thrombomodulin and immunothrombosis in SARS-CoV-2 infection |
title_fullStr |
Upregulation of pulmonary tissue factor, loss of thrombomodulin and immunothrombosis in SARS-CoV-2 infection |
title_full_unstemmed |
Upregulation of pulmonary tissue factor, loss of thrombomodulin and immunothrombosis in SARS-CoV-2 infection |
title_sort |
upregulation of pulmonary tissue factor, loss of thrombomodulin and immunothrombosis in sars-cov-2 infection |
publisher |
Elsevier |
series |
EClinicalMedicine |
issn |
2589-5370 |
publishDate |
2021-09-01 |
description |
Background: SARS-CoV-2 infection is associated with thrombotic and microvascular complications. The cause of coagulopathy in the disease is incompletely understood. Methods: A single-center cross-sectional study including 66 adult COVID-19 patients (40 moderate, 26 severe disease), and 9 controls, performed between 04/2020 and 10/2020. Markers of coagulation, endothelial cell function [angiopoietin-1,-2, P-selectin, von Willebrand Factor Antigen (WF:Ag), von Willebrand Factor Ristocetin Cofactor, ADAMTS13, thrombomodulin, soluble Endothelial cell Protein C Receptor (sEPCR), Tissue Factor Pathway Inhibitor], neutrophil activation (elastase, citrullinated histones) and fibrinolysis (tissue-type plasminogen activator, plasminogen activator inhibitor-1) were evaluated using ELISA. Tissue Factor (TF) was estimated by antithrombin-FVIIa complex (AT/FVIIa) and microparticles-TF (MP-TF). We correlated each marker and determined its association with severity. Expression of pulmonary TF, thrombomodulin and EPCR was determined by immunohistochemistry in 9 autopsies. Findings: Comorbidities were frequent in both groups, with older age associated with severe disease. All patients were on prophylactic anticoagulants. Three patients (4.5%) developed pulmonary embolism. Mortality was 7.5%. Patients presented with mild alterations in the coagulogram (compensated state). Biomarkers of endothelial cell, neutrophil activation and fibrinolysis were elevated in severe vs moderate disease; AT/FVIIa and MP-TF levels were higher in severe patients. Logistic regression revealed an association of D-dimers, angiopoietin-1, vWF:Ag, thrombomodulin, white blood cells, absolute neutrophil count (ANC) and hemoglobin levels with severity, with ANC and vWF:Ag identified as independent factors. Notably, postmortem specimens demonstrated epithelial expression of TF in the lung of fatal COVID-19 cases with loss of thrombomodulin staining, implying in a shift towards a procoagulant state. Interpretation: Coagulation dysregulation has multifactorial etiology in SARS-Cov-2 infection. Upregulation of pulmonary TF with loss of thrombomodulin emerge as a potential link to immunothrombosis, and therapeutic targets in the disease. Funding: John Hopkins University School of Medicine. |
topic |
Thrombosis Hemostasis Coagulation Ixolaris |
url |
http://www.sciencedirect.com/science/article/pii/S2589537021003497 |
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